tbuckley/cabot-search huggingface dataset:
Intratumor heterogeneity of positive lymph nodes provide a promising prognostic stratification factor for stage III colorectal cancer.
Authors: Xin Gao, Qi Zhang, Tao Yu, Shiyao Zhang, Jian Liu, Tong Liu, Gang Liu
Journal: Journal of Clinical Oncology (2022)

e15554 Background: Stage III colorectal cancer (CRC) is defined as patients with regional positive lymph nodes (pLN) but without distant metastasis, including stage IIIA, IIIB, IIIC. The prognosis of patients with stage III CRC varies dramatically, with 5-year survival rates ranging from 80 percent to 30 percent form stage IIIA to IIIC CRC, that does not exactly to be fully explained by the difference in the number of pLN. Therefore, other prognostic indicators need to be identified to improve and personalize prognosis prediction for patients with stage III CRC. Intratumor heterogeneity (ITH) widely exists between primary and metastatic lesions of CRC, however, there have been few studies focused on ITH of pLN. Therefore, this study aims to explore whether ITH of pLN could serve as a novel prognostic stratification factor for stage III CRC. Methods: We retrospectively analyzed the Poly-G genotype to reconstruct high-confidence phylogenetic trees for 20 CRC patients using 317 accurately scraped biopsy (134 primary tumors, 66 lymph node metastases and 37 normal samples). Root diversity score (RDS) index was used to reflect ITH of pLN. The association among Poly-G mutation rates, RDS index and clinical pathological data was analyzed. The area under the receiver operating characteristic (ROC) curves were calculated and the cut-off valve was confirmed. Results: Poly-G mutations accumulate in the occurrence and development of CRC. Poly-G mutation rate was correlated with tumor grade, N stage and microsatellite state (all P &lt; 0.05), and had a certain correlation trend with age (P = 0.066). The results of multivariate Cox regression analysis showed that ITH of pLN was an independent risk factor for recurrence and metastasis which lead to a poor progression free survival (PFS). The area under the curve (AUC) was 76%, and the cut-off valve of RDS index was 0.25. We also found ITH of pLN was not associated with substages of stage III CRC, which indicated that ITH of pLN and the number of metastases are two different dimensions. Conclusions: ITH of pLN may provide a promising prognostic stratification factor for the patients with stage III CRC. A higher ITH of pLN indicates that subclones with distant metastasis potential might more likely to exist in the primary tumors, which lead to a poor PFS including recurrence and distant metastasis. In addition, ITH of pLN is not related to the number of lymph node metastases in stage III CRC, suggesting that ITH of pLN is promising to serve as a supplementary strategy of TNM staging for patients with Stage III CRC.
APEC: Efficacy and toxicity of anlotinib plus PD-1 inhibitors as later-line therapy in advanced/metastatic esophageal squamous cell carcinoma (ESCC): A retrospective real-world study.
Authors: Jun Liu, Xiumei Ma, Jianguo Wu, Ming Zhang, Hongxuan Li, Yan Cheng, Xiaolong Fu
Journal: Journal of Clinical Oncology (2022)

e16014 Background: Anlotinib has been approved in ESCC treatment because of its good tolerance and efficacy. Antiangiogenic target therapy plus immunotherapy has been initially recognized, whereas the data on the third &amp; above line is still unknown. We aimed to retrospectively analyze the effect of anlotinib plus PD-1 inhibitor as later-line therapy on the survival of ESCC in the real world. (APEC, NCT 04984096). Methods: Retrospective data analysis was performed on ESCC patients (pts) treated with anlotinib plus PD-1 inhibitors as later-line therapy between Sep 2019 and Nov 2021 at Shanghai Chest Hospital, China. Demography, previous treatment, performance status, pathological classification, comorbidities, and distant metastatic organ status were collected. Progression free survival (PFS) was the primary end point of this study. The secondary end points were objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Tumor response was assessed per RECIST version 1.1 by the investigators. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results: There were 21 pts in the cohort. The average age was 61.5 (range 48-77) years old, and 95.2% patients were male. 7 cases (33.3%) had comorbidities. 2 cases (9.5%) had other tumor history. In addition, 19 pts (90.5%) had received radiotherapy, 21 pts (100.0%) had received chemotherapy and 19 pts (90.5%) had received immunotherapy. Among all pts, 1 patient achieved complete response (CR), 6 pts partial response (PR), 10 pts stable disease (SD), illustrating an ORR of 33.3 % and a DCR of 81.0%. Median PFS reached 8.1 months (95%CI 3.8-12.4) while median OS was not reached. All grades of TRAEs occurred in 95.2% pts and 90.5% were grade 1-2. Of note, grade 3-4 hematological toxicity (lymphocytopenia) was reported in only 2 patient (9.5%). All AEs were resolved after symptomatic treatment. Conclusions: Our data suggest that treatment with anlotinib plus PD-1 inhibitors as later-line therapy can result in curative effect of ESCC, which can achieve promising ORR, DCR and PFS with mild toxicity. To our knowledge, this is the first analysis to demonstrate the benefits of anlotinib plus PD-1 inhibitors as later-line therapy in ESCC. The data suggests that anlotinib plus PD-1 inhibitor is a new treatment in ESCC pts, and further validation in a larger cohort is needed. Clinical trial information: 04984096.
Optimizing the prostate biopsy template: Additional value of contralateral and ipsilateral systematic biopsies in patients with an unilateral lesion on magnetic resonance imaging
Authors: A. Jager, L.A.M.J.G. van Riel, A.W. Posterma, T.M. de Reijke, H.P. Beerlage, T.M. van der Sluis, J.R. Oddens
Journal: European Urology (2022)
Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy
Authors: Michael Hwang, Jenna Vanliere Canzoniero, Samuel Rosner, Guangfan Zhang, James R White, Zineb Belcaid, Christopher Cherry, Archana Balan, Gavin Pereira, Alexandria Curry, Noushin Niknafs, Jiajia Zhang, Kellie N Smith, Lavanya Sivapalan, Jamie E Chaft, Joshua E Reuss, Kristen Marrone, Joseph C Murray, Qing Kay Li, Vincent Lam, Benjamin P Levy, Christine Hann, Victor E Velculescu, Julie R Brahmer, Patrick M Forde, Tanguy Seiwert, Valsamo Anagnostou
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor–immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade. Methods Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance. Results Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts. Conclusions Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.
The additional role of Standard prostate biopsy combined to Target biopsy in biopsy naïve patients after radical prostatectomy: Results of a prospective randomized clinical trial
Authors: E. Checcucci, M. Manfredi, D. Amparore, S. De Cillis, F. Piramide, G. Volpi, A. Piana, A. Pecoraro, S. Granato, P. Verri, S. Piscitello, M. Burgio, L. Ola, J. Meziere, A. Quarà, E. Cisero, E. Dibilio, C. Fiori, S. De Luca, F. Porpiglia
Journal: European Urology (2022)
DIPG-57. A systems biology approach to defining and targeting master regulator dependencies from bulk and single-Cell RNA-seq in diffuse midline glioma (DMG)
Authors: Ester Calvo Fernández, Junqiang Wang, Aaron Griffin, Hanna Minns, Hong-Jian Wei, Xu Zhang, Luca Szalontay, Prabhjot Mundi, Cheng-Chia Wu, Robyn Gartrell, Stergios Zacharoulis, Andrea Califano, Jovana Pavisic
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline glioma (DMG) are fatal pediatric brain tumors with no effective systemic therapies. Molecular profiling demonstrates epigenetic dysregulation and heterogeneity, and novel approaches are needed to identify promising drugs and drug combinations. We used network-based computational analysis of RNA-seq to discover Master Regulator (MR) proteins that represent targetable, mechanistic determinants of distinct DMG cell states. We reverse-engineered the first DMG-specific regulatory network from 122 publicly available DMG RNA-seq profiles with ARACNe. Using this network, we measured sample-specific protein activity based on differential expression of their targets via VIPER. Activity-based clustering identified two clusters showing a trend in survival differences (&amp;gt;1 year, by χ2). The most activated MRs (i.e., TOP2A, CENPF, BUB1B, FOXM1, GTSE1, MKI67, E2F8), relative to normal caudate tissue, were enriched in cell cycle regulation members. The cluster with worse outcomes had significantly higher activity. Targetable MRs activated in subsets of patients () included TOP2A, CHEK1, CDK2, and EZH2. RNA-seq profiles were generated in two DMG cell lines following perturbation with ~400 oncology drugs, and used to identify drugs that invert MR activity profiles with the OncoTreat algorithm. We identified four pharmacotypes, and predicted sensitivity to HDAC, proteosome, EGFR, MEK, and PI3K inhibitors (), amongst others, consistent with published DMG high-throughput drug screens. To dissect intra-tumor heterogeneity, we measured protein activity from published single-cell RNA-seq profiles of 6 DMG patients, using single-cell based regulatory networks. Preliminary activity-based analysis identified 6 cell states representing distinct stages of differentiation/proliferation, including an oligodendrocyte precursor cell-like proliferative state whose MRs overlapped with bulk data (i.e. TOP2A, CENPF, FOXM1, E2F8, ZWINT, CCNA2), suggesting this as a key regulatory module. We are identifying cell state-specific MR-inverter drugs with OncoTreat to ultimately suggest drugs and drug combinations that collapse the transcriptional program and induce tumor kill for validation in MR-matched preclinical DMG models.
Deficit Accumulation Frailty Index (DAFI) scores and acute myeloid leukemia outcomes.
Authors: Catherine Lai, Olivia Conway, Minji Lee, Jennifer Le-Rademacher, Jeanne S. Mandelblatt, Heidi D. Klepin
Journal: Journal of Clinical Oncology (2022)

12040 Background: Novel strategies are needed to assess frailty in the context of therapy decisions for older adults with acute myeloid leukemia (AML). Our objectives were to describe pre-treatment DAFI scores for older AML patients treated on clinical trials and explore their relationship with treatment outcomes. Methods: We conducted a exploratory analysis utilizing data from two clinical trials of adults aged ≥60 years with newly diagnosed AML (Alliance/CALGB 11001 [intensive therapy] and Alliance/CALGB 11002 [non-intensive therapy]). We included the subset of patients in each trial enrolled on geriatric assessment companion studies (Alliance/CALGB 361006, 361101). A DAFI score was calculated for each patient using 51 variables including demographic, geriatric assessment, and laboratory data derived from the geriatric assessment. Individuals with ≥90% items were included (consistent with other studies); DAFI scores ranged from 0 to 1 and were evaluated using established categories (0- &lt;.2 [robust]; 0.2-&lt;.35 [pre-frail]; 0.35+ [frail]) and as a continuous score. Associations between DAFI scores and toxicity and overall survival (OS) were evaluated with Fisher’s exact-testing and Kaplan Meier/cox proportional hazards, respectively. Results: The median age was 68 years (range 61, 82) and 72 years (range 61, 92) for those getting intensive (N=31) and less intensive therapy (N= 75), respectively. Individuals in the intensive study had a median pre-treatment DAFI score of 0.15 (range 0.05, 0.31) and were all categorized as robust (75%) or pre-frail (25%). There was no significant difference in median OS (14.6 vs. 14.7 months) or non-hematological grade 3+ adverse events (AEs; 85% vs. 89%) between robust vs. pre-frail individuals in this trial, respectively. However, pre-frail adults experienced a trend towards greater grade 4 non-hematological toxicity than robust individuals (67% vs 26%, p=0.05). In the non-intensive trial, the median DAFI score was 0.24 (range 0.04, 0.48) and most individuals were pre-frail (49.3%) or frail (17.3%). Non-hematologic grade 3+ AEs did not vary by DAFI group, 88% robust, 95% pre-frail, and 77% frail (p=0.15). Median OS was 7.4, 10.8, and 6.3 months for robust, pre-frail, and frail respectively (p=0.17). Adjusting for age, each 0.1 increase in DAFI score was associated with increased mortality hazard (HR 1.8, 95% CI 1.0-3.2). Conclusions: DAFI score calculation provides a potential novel strategy for categorization of frailty in AML. In our assessment, higher DAFI scores were associated with toxicity during intensive induction and mortality in the less intensive setting. This method should be studied in larger samples randomized by treatment intensity. Support: UG1CA189823; Bayer Healthcare/Berlex (CALGB 11001); NCT01253070 (CALGB 11001). Clinical trial information: NCT01253070, NCT01420926.
Real-world outcomes associated with bevacizumab combined with chemotherapy in platinum-resistant ovarian cancer.
Authors: Gordon Taylor Moffat, Weidong Kong, Christopher M. Booth, Josee-Lyne Ethier
Journal: Journal of Clinical Oncology (2022)

5555 Background: In the pivotal Aurelia study, addition of bevacizumab (bev) to physician’s choice chemotherapy (paclitaxel, liposomal doxorubicin or topotecan) for platinum-resistant (PL-R) ovarian cancer (OC) was associated with improved progression-free survival (PFS; 6.7 vs 3.4 mos; hazard ratio (HR) 0.48, p = 0.001) but not overall survival (OS; 16.6 vs 13.3 mos HR 0.85, p = 0.174); the latter finding may relate to extensive crossover. In an exploratory subgroup analysis by treatment arm, benefits were particularly marked for bev + paclitaxel where median PFS (mPFS) increased from 3.9 to 10.4 mos (HR 0.46; 95%CI 0.30-0.71) and increases in OS approached statistical significance (HR 0.65; 95%CI, 0.42-1.02; 22.4 v 13.2 mos). Here we describe utilization of bev for PL-R OC and outcomes in routine clinical practice. Methods: The Ontario Cancer Registry and the New Drug Funding Program databases were utilized to identify all patients treated with bev plus chemotherapy (paclitaxel, liposomal doxorubicin or topotecan) for PL-R OC following its approval in 2017. Time on treatment (ToT) was defined as time from first to last bev treatment; this was used as a surrogate for PFS in routine practice. Median OS (mOS) was determined using the Kaplan-Meier method. Factors associated with ToT and OS were identified using a Cox proportional hazard model. A before and after comparison analysis was performed to determine mOS for patients treated pre- (2011-2017) and post-bev (2017-2019) approval. Results: From Oct 2017 to Dec 2019, 180 patients received bev + chemotherapy for first-line PL-R OC. Mean age was 63 years old, and 80% had serous OC. Bev was most often combined with liposomal doxorubicin (64 %) followed by paclitaxel (34%) and topotecan (2%). Median ToT was 3 months and OS was 11 months. ToT and OS were longer in patients who received paclitaxel as chemotherapy backbone (5 mos [ToT]; 14 mos [OS]) than those who received bev with liposomal doxorubicin (2 mos; 9 mos) or topotecan (2 mos; 6 mos). In multivariable models, ToT was superior in patients who received bev + paclitaxel than bev + liposomal doxorubicin (HR 0.40; 95%CI 0.28-0.57; p &lt; 0.0001), and worse with longer time from diagnosis to bev start (1.03; 1.01-1.05; p = 0.0120). OS was also significantly longer in those who received paclitaxel vs liposomal doxorubicin (HR 0.54; 95%CI 0.30-0.98; p = 0.043). In a before and after analysis, patients treated in the pre- (n = 1290) and post-bev (n = 360) era had mOS of 8 and 9 months respectively. Post mOS increased for patients receiving paclitaxel (7 vs 12 months) but not with liposomal doxorubicin (9 vs 7 months). Conclusions: ToT and OS associated with bev for PL-R OC are shorter in a real-world population compared to results reported in AURELIA. ToT and OS were longer with bev + paclitaxel than with other chemotherapy agents.
Platelet-to-Lymphocyte ratio (PLR) as a predictive marker in HER2 positive metastatic breast cancer patients treated with first-line trastuzumab therapy.
Authors: Zi-Ru Fang, Xia-Bo Shen, Jia-Yi Wu, Ke-Yu Chen, Xi-Ying Shao, Xiaojia Wang
Journal: Journal of Clinical Oncology (2022)

e13024 Background: The immune system reveals to play a pivotal role in HER2 positive breast cancer responsiveness to trastuzumab therapy. The platelet-lymphocyte ratio (PLR) is representative blood markers of systemic inflammatory responses. It is suggested as an immunity biomarker in gastric, lung cancer and other cancers, but is less well known in breast cancer. The aim of this study is to investigate the predictive role of PLR in HER2 positive metastatic breast cancer patients treated with first-line trastuzumab therapy. Methods: This study retrospectively includes 287 HER2 positive metastatic breast cancer patients with first-line trastuzumab therapy in Cancer Hospital of the University of Chinese Academy of Science from January 2010 to November 2021. The Peripheral blood cell count of these patients before trastuzumab treatment is evaluated to calculate PLR. All patients are separated into PLR high or PLR low cohort according to cut-off value defined as median value. Median value of PLR is 154.5, more than 154.5 is defined by PLR high , otherwise defined as PLR low . Kaplan–Meier curves is performed to assess progression-free survival (PFS). Univariate and multivariate analyses were performed using a logistic regression model. Results: Of 287 patients, 228 patients’ peripheral blood cell count were available. 114 patients are PLR high and 114 patients are PLR low . Patients with PLR high achieved a significantly worse PFS compared to those with PLR low (median PFS: 8.47 months vs.9.92 months, HR:1.475, 95% CI:1.068-2.038, P = 0.014). Besides, mean corpuscular volume (&lt; 89.2fL), lymphocyte (&lt; 1.3), mean hemoglobin (&lt; 30PG) are also related to worse PFS ( P= 0.003,0.033,0.055,respectively). Importantly, PLR high , mean corpuscular volume, remain independent predictors in the multivariate COX analysis (HR 0.689,95%CI 0.493-0.962, P = 0.028;HR1.646,95%CI 1.177-2.302, P = 0.004). Conclusions: Patients with pre-treatment PLR high showed less sensitivity to trastuzumab therapy for metastatic breast cancer patients independent of other molecular characteristics. The pre-treatment PLR levels might serve as a predictive biomarker for HER2 positive breast cancer with trastuzumab therapy.
The Hu2G10 mAb targets the cleaved-activated form of Trop-2 and exploits vulnerability of multiple human cancers.
Authors: Saverio Alberti, Marco Trerotola, Emanuela Guerra
Journal: Journal of Clinical Oncology (2022)

e14548 Background: FDA granted accelerated approval to the anti-Trop-2 sacituzumab govitecan-hziy (TRODELVY) antibody-drug conjugate (ADC), for patients with metastatic triple-negative breast cancer. Skin rash and mucosal inflammation were, though, dose-limiting toxicities of other high-effectiveness anti-Trop-2 antibodies, and impeded their development. These adverse events appeared as on-target/off-cancer effects, related to the expression of Trop-2 by normal tissues. Trop-2 is a transmembrane glycoprotein (E. Guerra et al., The Trop-2 signalling network in cancer growth. Oncogene 32, 1594-1600 (2013)), that is cleaved and activated by ADAM10 to induce cancer growth and metastatic diffusion (M. Trerotola et al., Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia 23, 415-428 (2021); E. Guerra et al., Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer. Neoplasia 23, 898-911 (2021)). This cleavage causes a spatial rearrangement of the extracellular portion of Trop-2 and exposes hidden, activation-specific epitopes. We succeeded in generating monoclonal antibodies (mAbs) capable of recognizing these cancer-exposed sites. Methods: Most Trop-2-targeted approaches are based on anti-Trop-2 mAbs that recognize a single immunodominant epitope. Such mAbs have limited therapeutic index. We removed the immunodominant epitope by deletion mutagenesis, and optimized breadth of immune response, by immunizing mice with recombinant proteins with diverse end-glycosylation patterns. Screening for cancer-specific mAbs was performed on mutagenized Trop-2, by cell-based ELISA assays, bio-layer interferometry, flow cytometry and fluorescence microscopy. Results: mAbs were obtained that efficiently bound Trop-2 expressing cancer cells and were able to inhibit cell growth in vitro. We humanized the 2G10 mAb into the Hu2G10 IgG1, with an affinity for recombinant, cancer-specific, cleaved Trop-2 that is several orders of magnitude higher than existing competitor mAbs. In vivo the naked Hu2G10 antibody was effective at inhibiting the growth of breast, colon, ovary and prostate cancers. In the ADC setting Hu2G10 drove high anticancer specificity and effectiveness. Conclusions: Hu2G10 shows unprecedented specificity and efficacy, for best-in-class anti-Trop-2 anticancer therapy.